Various types of delivery capsules have been developed for the controlled and sustained release of beneficial agents by diffusion through the capsule wall. The rate of release of the beneficial agent is controlled by combining the agent with an inert core material to a specified dilution and/or by formulating and manufacturing the membrane used to form the capsule wall in a manner which will result in the desired permeability. Polymeric membranes can be varied by such means as varying the degree of crosslinking or by using block copolymers and varying the relative amounts of the different blocks. Further control of the release rate can be obtained by varying the membrane thickness and total exposed surface area (i.e., the size of the capsule).
Certain therapies or regimens require, or would benefit from, the administration of more than one beneficial agent at the same time. This is true for the administration of a variety of drugs, medicaments and nutriments, in a range of environments extending from veterinary medicine to human drug administration as well as non-physiological environments. In some cases, particularly physiological environments, the two or more beneficial agents are most effective when they are administered at specified rates relative to each another. Whether the ratio of these specified rates is 1.0 (on a mole or weight basis) or something other than 1.0, deviations from the specified ratio can result in a loss of effectiveness, the inducement of undesirable side effects, or in some cases toxicity.
The placement of a blend of the beneficial agents in a single capsule in a proportion equal to the desired delivery rate ratio will not always achieve the desired result. In many cases, the agents will not diffuse together through the capsule membrane at the same ratio as they exist in the blend. The ratio would instead be dependent on the inherent ratio of the normalized permeation rates for the beneficial agents through the membrane. Flexibility would therefore be limited to the selection of suitable polymer candidates for the membrane, and the range of, and degree of control over, the delivery rate ratio which one might obtain in so doing is extremely limited.
For beneficial agents which are solid, a delivery rate approaching zero-order for any single agent over the life of the capsule is achieved by combining the agent with a liquid, semi-solid or solid solvent in the capsule, with the amount of agent present exceeding the solubility limit of the agent in the solvent. Release of the agent from the capsule in such a system involves diffusion of the dissolved agent through the solvent, across the solvent/membrane interface and through the membrane for release, while undissolved agent simultaneously dissolves into the solvent to replace the released agent, thereby maintaining a substantially constant level of agent dissolved in the solvent (i.e., the saturation concentration). For blended agents, the dominant factors in determining the delivery rate ratios will be the rates of dissolution of the agents in the solvent, the rates of diffusion of the agent through the solvent, and the rates of diffusion of the agents through the membrane. These factors are variable only by the choice of solvent and membrane, and when a common solvent and a common membrane material are used, the range of delivery rates which one can obtain is limited even further.
Alternatively, the need for maintaining a specified delivery rate ratio can be met by using a separate capsule for each beneficial agent. This is clearly undesirable, however, for those capsules designed for implantation subcutaneously or in a vesicle or organ of a living animal or human, since the presence of two or more capsules will compound the disruption which even a single capsule might create in the normal physiological activity of that vesicle or organ. In addition, if one capsule malfunctions, the desired delivery ratio will be lost. Further, complete therapy in a single implantable capsule is more acceptable to patients and more efficient to insert and remove, with both humans and animals.